Lymphangioleiomyomatosis (LAM) is a rare lung disease. Some LAM occurances are associated with mutations in the tuberous sclerosis complex (TSC) locus. LAM occurs almost exclusively in women, usually of childbearing age. There are two types of LAM, sporadic LAM and LAM/TSC which is LAM that frequently occurs in patients who have TSC.
LAM is characterized by the proliferation of abnormal smooth muscle-like cells throughout the lungs, in the bronchioles, alveolar septa, perivascular spaces, and lymphatics, resulting in the obstruction of small airways that leads to pulmonary cyst formation and pneumothorax, and lymphatics that leads to chylous pleural effusion.
TSC is a rare multi-system genetic disease that results in the growth of nonmalignant tumors in the brain and on other vital organs such as the kidneys, heart, eyes, lungs, brain, and skin. A combination of symptoms may include seizures, developmental delay, behavioral problems, skin abnormalities, and lung and kidney disease. TSC is caused by a mutation of either of two genes, TSC1 and TSC2, with the TSC2 mutation being the more typical TSC mutation. The mutations in the TSC locus tend to be negative mutations that lead to no or reduced amount of functional TSC 1 or 2 gene product. This in turn leads to a deregulation of the mTOR signaling pathway.
The mammalian target of rapamycin (mTOR) signaling pathway is a major player controlling cell growth and cell division. The kinase, mTOR, is a master regulator of protein synthesis that couples nutrient sensing to cell growth. Defects in the mTOR signaling pathway can result in loss of control in cell growth and cell division. For example, two proteins, hamartin and tuberin, are known to be involved in the control of cell growth and cell division via their effects on the mTOR signaling pathway. Hamartin and tuberin function as a complex to interact with Rheb GTPase, thereby sequestering it from activating mTOR signaling. Mutations at the TSC1 and TSC2 loci which codes for hamartin and tuberin respectively result in the deregulation of the mTOR signaling pathway resulting in increased mTOR signaling. This in turn leads to a loss of control of cell growth and cell division, and subsequently a predisposition to forming tumors.
High percentages (60-80%) of TSC patients have benign tumors in the kidneys called angiomyolipomas (AML) which frequently causing hematuria. These tumors are composed of vascular tissue (angio-), smooth muscle (-myo-), and fat (-lipoma). Although benign, AML may grow such that kidney function is impaired or the blood vessels may dilate and burst leading to catastrophic hemorrhage either spontaneously or with minimal trauma. Large AML can be treated with embolization.
In addition, TSC patients who have AML are predisposed to develop LAM in the lungs. The proliferating smooth muscle that occurs in the type of LAM seen in these patients (TSC-LAM) has been shown to represent clones of the smooth muscle in those patients' renal AML. It is believed to represent metastases of this “benign” tumor.
Leading causes of death in TSC patients include renal disease, brain tumor, LAM of the lung, and status epilepticus or bronchopneumonia in those with severe mental handicap. There is no current effective treatment for TSC or the consequential AML or LAM; treatment is mainly symptomatic management, e.g., everolimus (derivative of rapamycin) for the treatment of subependymal giant cell astrocytoma (brain tumor), vigabatrin for infantile spasm, ACTH for epilepsy and rapamycin for shrinking the tumors.
The clinical course of patients with LAM shows considerable variation. The disease can progress slowly, but ultimately leads to respiratory failure and death. The 10-year survival rate from the start of symptoms has been reported to range from 47-79% depending on the various studies. Current treatments include administration of rapamycin (also known as sirolimus, an mTOR inhibitor) for shrinking tumors, and therapies targeting the reproductive cycle of the women, e.g., progesterone, oophorectomy, tamoxifen, gonadotropin-releasing hormone (GnRH) agonists or analogues and androgen therapy. Although the mTORC1 inhibitor rapamycin has been shown to stabilize lung function and improved symptoms in these patients, the lung function tend to declined when rapamycin was discontinued. Improvement to the current repertoire of therapies for LAM and LAM/TSC are needed.